Increasing evidence demonstrates a crucial role of the innate immune system, and in particular natural killer (NK) cells, in the host's response against viral infection, including hepatitis C virus (HCV). Unlike other lymphocytes, NK cells lack specific antigen receptors, but eliminate target cells following the integration of complex signals from an arsenal of inhibitory and activating receptors upon ligation of several classical and non-classical major histocompatibility complexes (MHC) on the surface of target cells. The significant epidemiological association between better outcome from HCV infection and the combined expression of particular NK cell killer immunoglobulin-like receptor (KIR) genes together with their respective HLA class I ligand further emphasizes the potential importance of NK cells in the control of HCV infection. Interestingly, recent data has illustrated that mutations in peptides bound by HLA alleles can alter KIR recognition of target cells, supporting some degree of peptide-specificity to NK cell function. Furthermore, our preliminary data combining population host genomics with viral sequencing now suggests that KIR-associated mutations can be identified in HIV, suggesting that NK cells are capable of exerting selective pressures upon viruses. We hypothesize in this proposal that NK cells can drive HCV evolution, and that NK-driven mutations are impairing viral replication capacity and contributing to immune control. Thus, the overall objective of this proposal is to study the antiviral activity of NK cells and their impact on HCV evolution. The following specific aims will be addressed: (1) Identification of HCV sequence mutations associated with the expression of specific KIR/HLA compound genotypes;(2) Determine the impact of KIR/HLA-associated HCV sequence mutations on NK cell recognition;and (3) Determine the impact of KIR/HLA-associated HCV-sequence mutations on viral replication.